1. Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families
- Author
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Martin Oti, Bjørn Ivar Haukanes, Thandiswa Ngcungcu, Stine Buechmann-Moller, Tomasz Stokowy, Wayne Grayson, Olav Sundnes, Edward J. Oakeley, Fan Yang, Ivonne M.J.J. van Vlijmen-Willems, Han G. Brunner, Michèle Ramsay, Hans van Bokhoven, Robert Bruccoleri, Jiang Zhu, Thomas Morgan, Kari Merete Ersland, Bolan Linghu, Charlotte von der Lippe, Huiqing Zhou, Torunn Fiskerstrand, Frank Staedtler, Marc Sultan, Joost Schalkwijk, Jan Cezary Sitek, Vidar M. Steen, Joseph D. Szustakowski, Peter R. Hull, Nanguneri Nirmala, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA Klinische Genetica (5)
- Subjects
0301 basic medicine ,Epigenomics ,Male ,Cathepsin B ,DNA Glycosylases ,030207 dermatology & venereal diseases ,South Africa ,0302 clinical medicine ,Gene Duplication ,Gene expression ,Gene duplication ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Genetics (clinical) ,Genetics ,Regulation of gene expression ,integumentary system ,Norway ,ENCODING CYSTATIN-A ,Autosomal dominant trait ,Chromosome Mapping ,Skin Diseases, Genetic ,Pedigree ,GENOME ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,Enhancer Elements, Genetic ,MCF-7 Cells ,Female ,Molecular Developmental Biology ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Chromosomes, Human, Pair 8 ,Genetic Markers ,DNA Copy Number Variations ,DNA-SEQUENCING DATA ,Biology ,03 medical and health sciences ,EPIDERMAL DIFFERENTIATION ,medicine ,Humans ,Enhancer ,Gene ,OUDTSHOORN SKIN ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,KERATINOCYTES ,Keratosis ,medicine.disease ,Molecular biology ,GENE ,030104 developmental biology ,Gene Expression Regulation ,CHROMOSOME 8P22-P23 ,Erythema ,CATHEPSIN-L ,ERYTHROKERATOLYSIS-HIEMALIS ,Case-Control Studies ,Keratolytic winter erythema ,Epidermis - Abstract
Contains fulltext : 174194.pdf (Publisher’s version ) (Open Access) Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.
- Published
- 2017